Adeno-associated virus 2 infection in children with non-A–E hepatitis
Antonia Ho, Richard Orton, Rachel Tayler, Patawee Asamaphan, Vanessa Herder, Christopher Davis, L. Tong, Katherine Smollett, Maria Manali, Jay Allan, Konrad Rawlik, Sarah E. McDonald, Elen Vink, Louisa Pollock, Louise Gannon, Clair Evans, Jim McMenamin, Kirsty Roy, Kimberly Marsh, Titus Divala, Matthew T. G. Holden, Michael Lockhart, David Yirrell, Sandra Currie, Maureen O’Leary, David Henderson, Samantha J. Shepherd, Celia Jackson, Rory Gunson, Alasdair Maclean, Neil McInnes, Amanda Bradley-Stewart, Richard Battle, Jill A. Hollenbach, Paul Henderson, Miranda Odam, Primrose Chikowore, Wilna Oosthuyzen, Meera Chand, Melissa Shea Hamilton, Diego Estrada‐Rivadeneyra, Michael Levin, Nikos Avramidis, Erola Pairo‐Castineira, Véronique Vitart, Craig Wilkie, Aubrey J. Cunnington, Jethro Herberg, Myrsini Kaforou, Victoria Wright, Evangelos Bellos, Claire Broderick, Samuel Channon‐Wells, Samantha Cooray, Tisham De, Giselle D’Souza, Leire Estramiana Elorrieta, Rachel Galassini, Dominic Habgood-Coote, Shea Hamilton, Heather Jackson, James Kavanagh, Mahdi Moradi Marjaneh, Stephanie Menikou, Samuel Nichols, Ruud Nijman, Harsita Patel, Ivana Pennisi, Oliver Powell, Ruth Reid, Priyen Shah, Ortensia Vito, Elizabeth Whittaker, Clare Wilson, Rebecca Womersley, Amina Abdulla, Sarah Darnell, Sobia Mustafa, Pantelis Georgiou, Jesus-Rodriguez Manzano, Nicolas Moser, Ivana Pennisi, Michael J. Carter, Shane M. Tibby, Jonathan Cohen, Francesca Davis, Julia Kenny, Paul Wellman, Marie White, Matthew Fish, A.R. Jennings, Manu Shankar‐Hari, Katy Fidler, Dan Agranoff, Vivien Richmond, Mathew Seal, Saul N. Faust, Dan Owen, Ruth Ensom, Sarah McKay
Abstract
An outbreak of acute hepatitis of unknown aetiology in children was reported in Scotland1 in April 2022 and has now been identified in 35 countries2. Several recent studies have suggested an association with human adenovirus with this outbreak, a virus not commonly associated with hepatitis. Here we report a detailed case–control investigation and find an association between adeno-associated virus 2 (AAV2) infection and host genetics in disease susceptibility. Using next-generation sequencing, PCR with reverse transcription, serology and in situ hybridization, we detected recent infection with AAV2 in plasma and liver samples in 26 out of 32 (81%) cases of hepatitis compared with 5 out of 74 (7%) of samples from unaffected individuals. Furthermore, AAV2 was detected within ballooned hepatocytes alongside a prominent T cell infiltrate in liver biopsy samples. In keeping with a CD4+ T-cell-mediated immune pathology, the human leukocyte antigen (HLA) class II HLA-DRB1*04:01 allele was identified in 25 out of 27 cases (93%) compared with a background frequency of 10 out of 64 (16%; P = 5.49 × 10−12). In summary, we report an outbreak of acute paediatric hepatitis associated with AAV2 infection (most likely acquired as a co-infection with human adenovirus that is usually required as a ‘helper virus’ to support AAV2 replication) and disease susceptibility related to HLA class II status. A case–control study investigating the causes of recent cases of acute hepatitis of unknown aetiology in 32 children identifies an association between adeno-associated virus infection and host genetics in disease susceptibility.